My previous NIH sponsored studies and those of others have demonstrated that sodium channels in a variety of excitable membranes are modulated by antiarrhythmic drugs. The so-called quinidine-like class of drugs is really a much more heterogenerous and interesting group of drugs than was formerly thought to be the case. A number of important structure/activity relations (SAR) which govern such drug actions have been revealed by my previous work. A drug "solubility hypothesis" predicts just how much drug must be present to produce a given blocking effect during action potentials. A "size-solubility hypothesis" predicts just how long this drug-induced effect will last between action potentials. Investigations into the mechanisms for these observed SAR will now be focused upon. Sodium channel availability will be assessed using electrophysiological recording techniques, both microelectrode recordings from mammalian ventricle and direct voltage-clamp observations of sodium currents in amphibian skeletal muscle. Experiments will be aimed at (1) finding new SAR regarding open and inactive channel blocking, (2) finding out how both membrane and channel manipulations influence these SARs, and (3) looking in greater detail into the channel/drug interactions envisioned by the "modulated receptor hypothesis". The results of this proposed study should contribute significant new insights into drug design therapy for cardiac arrhythmias.